Preparation of 17 alpha-hydroxy steroids



Patented Dec. 15, 1953 PRERARATIQN. QE Z XDBJOXX" M EEQmS" Percy L.Julian, Maywood, and: Edwin; W: Meyers and: Isabella Rydens. C i a o). Ils. ass suo s; c. The Gliddenfi mnany, C euelandflhic. acesnoraticnofQhip No Drawing; Application May -lfl 194$,

SerialiNo. 93,638

Glaims (Cl. 260-3975) 1-. The present invention relatestothe producticn:of" 1-7 a-hydroxy steroids.

ofithe corticohormones. possess; a 17a-hy-. These hormones are at.presene commercially prepared by tedious and expensive droxy group.

extraction and! purification-methods from adrenal cortices. Syntheticmethods for introducing the-- l-Taehydroxy group: into steroid materialsobtainable: from other natural sources: have been pro-- posed, Fuchs andReichstein, Helv. Chem. Acta, 24-, 804,; (21 941.); Hegner andReichstein, Helv. Chem..Acta, 24, 828; 1941, but these have either been.exceedingly complex because of the multitude of steps, or have involvedtheuse of expen siveand. hazardous chemicals, such as: osmium tetroxide,Sarett, J. Biol. Chem. 162, 6013 1946 Sarett,.J A. C. S., 70:, 1454,(1948).

It is accordingly an object of the present invention to provide a novelmethod for introducing a l7a-hydroxy group into the steroid molecule.

Another object is to produce new intermediates valuable in the:synthesisof steroids; possessing cortical activity.

Other obiects will be apparent from the follow ing description.

It appeared that reduction of 16,17-oxidopregnene and pregnane compoundsmight lead to the introduction of the l'la-hydroxy group. However, theusual reducing treatments were found to be unsuitable.

It has now been found, however, that the dc,- sired compounds arereadily produced when the 16,17-oxido-compounds are reduced with lithiumaluminum hydride, LiA1I-I4.

The reaction may be represented by the following general equationEXAMPLE 1 Preparation of 16,17-omido--p1egnene-3/9-oZ-20- one acetate Asolution of 3.54 grams of A -pregnadiene-3flo1-20-one acetate in 20 ml.of CHCls was treated at ice bath temperature with a solution of 1.60 g.of bromine in 16 m1. of CHCls.

The chloroform solution was: then washed-with. water, 2% NaOl-I, wateranddriedu It was. then concentrated in vacuo toa whitecrystalline-solid.This solid. was. dissolved in-50|ml. of benzene. and treated with; v 50ml; of a benzene-solutioncontaining Bis-mg.-

centrated to a white crystalline solid which was debrominated with zincdust in ether-acetic acid solution. The ether solution was separated:from nc. washed: wi h; mates, dilutev s dium bi r om ate solution. watera d-d Af er con en ra- ZQ-One ac ate wascrrsta izedfr m m hano 1.6.? e1?. 15231.55 Q- Reduction of 16,17-oxido-pregnezmione acetate A s l i n.of" 1-0 s. 25 2 ox dp p eenen lo e acetate o ample. 1. 5.0 m ofnhydrous. ether was added'dropwise to a stirred suspension 500 o ith ualuminum hy ride .1 .50 ml. of ether. room te perature for one-ha t hourand a ref x f r one-ha1i' o The r action. mixture decomnos dfby slowaddi ion of. water. The ether y r wasw hed wi h 2 N su uric id. wate odum b c bonate so utio and. w t r T e white crystalline product,remaining after removal of solvent from the dried solution melted at-185 C. This material contains a mixture of the C-20 epimers of Apregnene-3fi, 17, 20- triol.

This material may be used directly for the preparation of l'la-hydroxyprogesterone. By bromination in methylene chloride, removal of solventin vacuo and then oxidation in acetic acid with chromic acid, followedby removal of bromine with chromous chloride there resulted a crudereaction product. By fractional crystallization and chromatography, thedesired l'la-hydroxy progesterone was isolated from this product.

EXAMPLE 3 The nature of the mixture obtained according to Example 2 wasdetermined by' oxidation with periodic acid. The product from 500 mg. ofthe oxide was oxidized with 833 mg. of periodic acid in acidulatedaqueous methanol. After 24 hours at room temperature, the mixture wasneutralized and distilled in 'vacuo. From the distillate there Themixture was h n. stirr d at.

was obtained acetaldehyde as the 2,4 dinitrophenylhydrazone, 50 mg. ororange plates, M. P. 164-16'7 C., which gave no depression in meltingpoint when mixed with authentic material.

The residue from the distillation was diluted with water and extractedwith ether. The extract was then washed with dilute HCl, water, diluteNaOH solution and water. After removal of ether from the dried solution,there remained an orange gum which was chromatographed on 15 g. ofactivated alumina. From the benzene-ether eluates there was obtained 10mg. of crude dehydroisoandrosterone, M. P. 138 C., after losing solventat 100 C. Crystallization from methanol gave white needles melting at148-149 C., which showed no depression in melting when mixed withauthentic dehydroisoandrosterone.

EXAMPLE 4-.

A -allopregnene-8fi-ol-20one acetate oxidized with perbenzoic acid andthe reaction product worked up as in Example 1 yields16,1'7-oxidoallopregnane-3fi-ol-20one acetate. This can then be reducedwith LiAlI-Ir and the reaction product decomposed with water as inExample 2. Working up the product as in Example 2 yields a mixture ofthe 20-epimeric allopregnane 3B- 17a20-triol (corticosteroids J andEXAMPLE 5 Preparation of M-pregnene-tpd7a,20-trioZs from the3-hydromy-oxido compound The 16,17-oxido-5pregnene-3p-ol-20-one acetateproduced in Example 1 was hydrolyzed to form the 3-hydroxy compoundwhich was then treated with lithium aluminum hydride as in Example 2.The reaction product was then decomposed with water and the reactionproduct worked up as in Example 2 to give a mixture containing the sameC-20 epimers as were produced in Example 2.

The foregoing examples will serve as illustrative of the type of steroidcompounds which can be employed. The compounds may be defined as being16,1'7-oxido-pregnanes and pregnenes, which may be substituted or not invarious positions in the nucleus. Thus, compounds containingsubstituents in the 6, 7, 11, 12, or other positions of the nucleus mayalso be employed, in addition to those having a substituent only at the3 position. Also, 16,17-oxid0 compounds containing unesterified OHgroups may be reduced according to the invention.

Reference is made to our application Serial No. 109,808, filed August11, 1949, wherein the A -16,17-oxido steroids, disclosed herein, andtheir preparation are claimed.

Having described the invention, what is claimed is:

1. The process which comprises reducing a. nuclearly unsaturated17-acetyl-16,1'7-oxidosteroid with lithium aluminum hydride.

2. The process which comprises reducing a. nuclearly unsaturatedl7-acetyl-16,1'7-oxidosteroid with lithium aluminum hydride anddecomposing the resulting product with an aqueous medium.

3. The process which comprises reducing a nuclearly unsaturated17-acetyl-16,17-oxido- 3p-hydroxy steroid with lithium aluminum hydride.

4. The process which comprises reducing 16,17- oxido 5pregnene-3fi-ol-20-one with lithium aluminum hydride.

5. The process which comprises reducing 16,17- oxido 5pregnene-3fi-ol-20-one with lithium aluminum hydride and thendecomposing the reaction product by treatment with an aqueous medium toform a mixture containing C-20 epimeric 5-pregnene 3,3,17a,20-triols.

6. The process which comprises reducing 16,17- oxido-5-pregnene3fl-ol-20-one acetate with lithium aluminum hydride.

7. The process which comprises reducing 16,17-oxido5-pregnene-3fi-ol-20-one acetate with lithium aluminum hydride andthen decomposing the reaction product by treatment with an aqueousmedium to form a mixture containing 0-20 epimeric S-pregnene3fi,17a,20-tli01$.

PERCY L. JULIAN. EDWIN W. MEYER. ISABELLE RYDEN.

References Cited in the file of this patent UNITED STATES PATENTS NameDate Butenandt Jan. 30, 1945 Logemann Mar. 2'7, 1945 OTHER REFERENCESNumber

1. THE PROCESS WHICH COMPRISES REDUCING A NUCLEARLY UNSATURATED17-ACETYL-16,17-OXIDIOSTEROID WITH LITHIUM ALUMINUM HYDRIDE.